The long-term objective of these studies is to develop an effective therapy for dominantly inherited, late onset, neurodegenerative diseases caused by expansions in CAG repeats. The CAG/polyglutamine expansion has been found to form the molecular basis for at least nine neurodegenerative diseases. These include Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), Machado-Joseph disease (MJD or SCA-3), dentatorubropallidoluysian atrophy (DRPLA), and spinocerebellar ataxias types 1, 2, and 6 (SCA-1, SCA-2, and SCA-6). In all cases, there is selective death of neurons in different brain regions and the clinical symptoms correlate with the affected regions. The function of most of these disease-causing proteins is unknown and the proteins appear to be functionally unrelated except for the polyglutamine tract. Expansion of the glutamine repeat in all these proteins appears to confer upon the disease protein a toxic gain-of-function that is selectively deleterious to neurons. The goal of the proposed research is to define a common relationship between these seven disease-associated gene products. We will test our hypothesis that proteolytic fragments derived from the seven polyglutamine containing proteins are pro-apoptotic, and that the pro-apoptotic phenotype is dependent upon cleavage of these proteins by cell death executioners, the caspases.